U.S. Pat. No. 4,954,526, issued on Sep. 4, 1990, discloses stabilized nitric oxide primary amine complexes which release nitric oxide in vivo and discloses that they are useful in treating cardiovascular disorders. U.S. Pat. No. 5,039,705, issued Aug. 13, 1991, discloses anti-hypertensive compositions of secondary amine-nitric oxide adducts which release nitric oxide in vivo and that they are useful in lowering blood pressure in mammals. U.S. patent application Ser. No. 07/585,793 filed on Sep. 20, 1990, discloses complexes of nitric oxide with polyamines which release nitric oxide in vivo in a sustained and controllable fashion, and discloses that the compounds are useful in treating cardiovascular disorders. U.S. patent application Ser. No. 07/743,892, filed on Aug. 12, 1991, discloses anti-hypertensive compositions of additional secondary aminenitric oxide adducts which release nitric oxide in vivo and which are disclosed to be useful in controlling blood pressure in vivo. U.S. patent application Ser. No. 07/423,279, filed on Oct. 18, 1989, discloses anti-hypertensive compositions and methods of lowering blood pressure in mammals, which each utilize certain active compounds containing an N-oxo-N-nitrosoamine substituent, the compounds are disclosed to decompose under physiological conditions to release nitric oxide in vivo. U.S. patent application Ser. No. 07/764,908, filed Sep. 24, 1991 discloses oxygen substituted derivatives of nucleophile-nitric oxide adducts which are prodrugs for nitric oxide release in vivo and Which are useful in the treatment of cardiovascular disorders.
Each of the above disclosed U.S. patents and U.S. patent applications is incorporated herein by reference in its entirety. None of the above U.S. patents and/or U.S. patent applications discloses that the nitric oxide complexes disclosed therein inhibit platelet aggregation.
Among the most widely used clinical antiplatelet agents is aspirin, which acts by inhibiting the cyclooxygenase enzymes responsible for the arachidonic acid cascade involved in platelet aggregation (GJ Roth et al, Proc. Nat. Acad. Sci. USA 72: 3073, 1975). Although the clinical efficacy of aspirin is clear [P Theroux et al, New England J. Med. 319: 1105, 1988; ISIS-2 (2nd International Study of Impact Survival) Collaborative Group, Lancet (2): 349-360, 1988], there are important disadvantages associated with its use, such as its aggravating effect on peptic ulcers. Recently, nitric oxide has been identified as a natural messenger molecule in the inhibition of platelet aggregation via the guanylate cyclase/cyclic GMP system (BT Mellion et al, BLOOD 57:946-955, 1981).